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WO2005013682A2 - Modele animal utile pour l'analyse des metastases tumorales - Google Patents

Modele animal utile pour l'analyse des metastases tumorales Download PDF

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Publication number
WO2005013682A2
WO2005013682A2 PCT/US2004/019697 US2004019697W WO2005013682A2 WO 2005013682 A2 WO2005013682 A2 WO 2005013682A2 US 2004019697 W US2004019697 W US 2004019697W WO 2005013682 A2 WO2005013682 A2 WO 2005013682A2
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Prior art keywords
cancer
metastasis
factor
protein
subunit
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WO2005013682A3 (fr
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Masato Nakamura
Yasuyuki Ohnishi
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Central Institute for Experimental Animals
CENTER FOR ADVANCEMENT OF HEALTH AND BIOSCIENCE
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Central Institute for Experimental Animals
CENTER FOR ADVANCEMENT OF HEALTH AND BIOSCIENCE
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Priority to DE602004025706T priority Critical patent/DE602004025706D1/de
Priority to EP04776817A priority patent/EP1644732B1/fr
Priority to AT04776817T priority patent/ATE458997T1/de
Priority to AU2004263079A priority patent/AU2004263079A1/en
Priority to CA002531916A priority patent/CA2531916A1/fr
Priority to JP2006518659A priority patent/JP4663634B2/ja
Publication of WO2005013682A2 publication Critical patent/WO2005013682A2/fr
Publication of WO2005013682A3 publication Critical patent/WO2005013682A3/fr
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    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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    • A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
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    • A61K49/0008—Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/715—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
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    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57438—Specifically defined cancers of liver, pancreas or kidney
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A01K2217/07—Animals genetically altered by homologous recombination
    • A01K2217/075—Animals genetically altered by homologous recombination inducing loss of function, i.e. knock out
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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    • A01K2267/03—Animal model, e.g. for test or diseases
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    • C12N2799/00—Uses of viruses
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    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers

Definitions

  • the present invention concerns a transgenic animal model for the analysis of tumor metastasis.
  • the present invention provides methods for the study of tumor metastasis, including the analysis of metastasis of cancer, in a transgenic (including knock out) rodent, such as mouse model.
  • mice such as athymic nude mice, C.B-17/severe combined immunodeficiency (scid) mice and NOD/SCID mice have been widely used as animal models in cancer metastasis research (Bruns et al, Int. J. Cancer 10:102(2):101-8 (2002); Ohta et al, Jpn. J Cancer Chemother. 23:1669-72 (1996); Jimenez et al, Ann. Surg. 231 :644-54 (2000)).
  • mouse models have been used for preclinical testing of new cancer drugs and for the detection of metastasis related genes (Bruns et al, supra; Ohta et al, supra; Jimenez et al.
  • NOG transgenic mice have been described as an excellent recipient mouse model for engraftment of human cells (Ito et al, Blood 100:3175-82 (2002)), and for the study of the in vivo development of human T cells from CD34(+) cells (Saito et al. Int. Immunol. 14:1113-24 (2002)).
  • CBSC human cord blood stem cells
  • CBSC CBSC were differentiated to T lymphocytes and migrated to the peripheral lymphoid organs (Yahata et al, J. Immunol. 169:204-9 (2002)).
  • Metastasis including hepatic metastasis, is often observed in human cancer, including pancreatic cancer even in early stage, cancers of the digestive tract, including colorectal cancer and gastrointestinal cancer, lung cancer, and the like, and is one of the most frequent causes of cancer deaths.
  • New strategies are necessary to manage cancer metastases, which, in turn, require the availability of appropriate and efficient animal models. Accordingly, there is a great unmet need for reliable animal models that enable the study of metastasis.
  • the present invention concerns a method for testing tumor metastasis, comprising the steps of (a) inoculating a tumor cell from a metastatic tumor or tumor cell line into a NOD/SCID/ ⁇ c nul1 animal, such as rodent, preferably mouse, and (b) monitoring the development of tumor metastasis.
  • the tumor is cancer, such as, for example, pancreatic cancer, prostate cancer, breast cancer, colorectal cancer, gastrointestinal cancer, colon cancer, lung cancer, hepatocellular cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, cancer of the urinary tract, thyroid cancer, renal cancer, carcinoma, melanoma, or brain cancer.
  • the metastasis is hepatic, bone, brain or lung metastasis, in particular, hepatic metastasis.
  • the tumor cell is from a metastatic tumor cell line, which can, for example, be a strongly, moderately or lightly metastatic tumor cell line.
  • Pancreatic cancer cell lines suitable for the present invention include, for example, MIAPaCa-2, AsPC-1, PANC-1, Capan-1, and BxPC-3. Inoculation can be performed, for example, by portal vein injection.
  • at least about lxlO 2 cells are inoculated, without any other pretreatment including irradiation or cytokine-medication.
  • at least about 1x10 cells are inoculated.
  • the invention concerns a method for testing a candidate anti-metastasis compound, comprising (a) administering said candidate compound to a NOD/SCID/ ⁇ c nul1 animal, such as a rodent, e.g. a mouse which has developed tumor metastasis, and (b) monitoring the effect of said candidate compound on said tumor metastasis.
  • the test compound can be any kind of molecule, including, without limitation, a peptide, polypeptide, antibody or a non-peptide small molecule.
  • the invention concerns a method comprising: (a) introducing into a NOD/SC_D/ ⁇ c nu11 animal, including rodent, such as a mouse a foreign gene, and (b) monitoring the expression of the foreign gene in the animal.
  • the foreign gene be introduced into the animal, e.g. mouse by any method of gene transfer, including, without limitation, by a viral vector.
  • the foreign gene is a gene which is differentially expressed in tumor metastasis, such as hepatic metastasis.
  • the gene can, for example, be selected from TIS1 IB protein; prostate differentiation factor (PDF); glycoproteins hormone ⁇ - subunit; thrombopoietin (THPO); manic fringe homology (MFNG); complement component 5 (C5); jagged homolog 1 (JAG1); interleukin enhancer-binding factor (ILF); PCAF-associated factor 65 alpha; interleukin- 12 ⁇ -subunit (IL-12- ⁇ ); nuclear respiratory factor 1 (NRF1); stem cell factor (SCF); transcription factor repressor protein (PRDI-BF1); small inducible cytokine subfamily A member 1 (SCYAl).
  • TIS1 IB protein prostate differentiation factor
  • PDF glycoproteins hormone ⁇ - subunit
  • thrombopoietin thrombopoietin
  • MFNG manic fringe homology
  • C5 complement component 5
  • JAG1 jagged homolog 1
  • IEF interleukin enhancer-binding factor
  • transducin ⁇ 2 subunit X-ray repair complementing defective repair in Chinese hamster cells 1; putative renal organic anion transporter 1; Gl/S-specific cyclin E (CCNE); retinoic acid receptor- ⁇ (RARG); S-100 calcium-binding protein Al; neutral amino acid transporter A (SATT); dopachrome tautomerase; ets transcription factor (NERF2); calcium- activated potassium channel ⁇ -subunit; CD27BP; keratin 10; 6-O-methylguanine-DNA- methyltransferase (MGMT); xeroderma pigmentosum group A complementing protein (XPA); CDC6-related protein; cell division protein kinase 4; nociceptin receptor; cytochrome P450 XXVIIB1; N-myc proto-oncogene; solute carrier family member 1 (SLC2A1); membrane- associated kinase mytl; casper, a FADD- and caspase-related inducer of a
  • the animal e.g. mouse carrying a gene marker of tumor metastasis is treated with a candidate anti-metastasis compound, and the expression level of the gene marker or its expression product as a result of the treatment is monitored.
  • the invention concerns an array comprising at least one gene, or its expression product, selected from the group consisting of TIS1 IB protein; prostate differentiation factor (PDF); glycoproteins hormone ⁇ -subunit; thrombopoietin (THPO); manic fringe homology (MFNG); complement component 5 (C5); jagged homolog 1 (JAG1); interleukin enhancer-binding factor (ILF); PCAF-associated factor 65 alpha; interleukin- 12 ⁇ - subunit (IL-12- ⁇ ); nuclear respiratory factor 1 (NRF1); stem cell factor (SCF); transcription factor repressor protein (PRDI-BF1); small inducible cytokine subfamily A member 1 (SCYAl), transducin ⁇ 2 subunit; X-
  • TIS1 IB protein prostate differentiation
  • the array displays at least 2, or at least 5, or at least 10, or at least 15, or at least 20, or at least 25 of the listed genes, or their expression products. In another embodiments, all genes that are overexpressed in tumor metastasis, or their expression products, are displayed. In another embodiment, all genes that are underexpressed in tumor metastasis, or their expression products, are displayed.
  • the invention concerns a method for predicting the likelihood of tumor metastasis in a subject comprising (a) determining the expression level of one or more RNA transcripts or their expression products in a biological sample comprising cancer cells obtained from said subject, wherein the RNA transcript is selected from the group consisting of TIS1 IB protein; prostate differentiation factor (PDF); glycoproteins hormone ⁇ -subunit; thrombopoietin (THPO); manic fringe homology (MFNG); complement component 5 (C5); jagged homolog 1 (JAG1); interleukin enhancer-binding factor (ILF); PCAF-associated factor 65 alpha; interleukin- 12 ⁇ - subunit (IL-12- ⁇ ); nuclear respiratory factor 1 (NRFl); stem cell factor (SCF); transcription factor repressor protein (PRDI-BF1); small inducible cytokine subfamily A member 1 (SCYAl), transducin ⁇ 2 subunit; X-ray repair complementing defective repair in Chinese hamster cells 1 ; put
  • the subject is preferably a human patient, and the biological sample preferably is a tumor sample obtained by standard procedure, such as, for example, biopsy.
  • Figures 1A and B illustrate the incidences of hepatic metastasis and the number of liver foci in NOG mice following the inoculation of lxlO 4 , lxlO 3 and lxlO 2 cells of the indicated pancreatic adenocarcinoma cells lines (MIAPaCa-2, AsPC-1, PANC-1, Capan-1, and BxPC-3.
  • MIAPaCa-2 pancreatic adenocarcinoma cells lines
  • AsPC-1 AsPC-1
  • PANC-1 AsPC-1
  • Capan-1 Capan-1
  • BxPC-3 pancreatic adenocarcinoma cells lines
  • tumor refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues.
  • cancer and cancerous refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.
  • cancer examples include but are not limited to, pancreatic cancer, prostate cancer, breast cancer, colorectal cancer, gastrointestinal cancer, colon cancer, lung cancer, hepatocellular cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, cancer of the urinary tract, thyroid cancer, renal cancer, carcinoma, melanoma, and brain cancer.
  • the term "metastasis” is used herein in the broadest sense and refers to the spread of tumor, e.g. cancer from one part of the body to another. Tumors formed from cells that have spread are called secondary tumors, and contain the same type of cells as the original (primary) tumor.
  • prostate cancer that has metastasized to liver or bone is not liver or bone cancer, rather metastasized prostate cancer, as it still contains prostate cancer cells, regardless of their location.
  • the "pathology" of cancer includes all phenomena that compromise the well-being of the patient. This includes, without limitation, abnormal or uncontrollable cell growth, metastasis, interference with the normal functioning of neighboring cells, release of cytokines or other secretory products at abnormal levels, suppression or aggravation of inflammatory or immunological response, neoplasia, premalignancy, malignancy, invasion of surrounding or distant tissues or organs, such as lymph nodes, etc.
  • differential gene refers to a gene whose expression is at a higher or lower level in one cell or cell type relative to another, or one patient or test subject relative to another.
  • differential gene expression can occur in normal cell/tissue/patient relative to a corresponding diseased cell/tissue/patient, or can reflect differences is gene expression pattern between different cell types or cells in different stages of development.
  • the terms also include genes whose expression is activated to a higher or lower level at different stages of the same disease.
  • a differentially expressed gene may be either activated or inhibited at the nucleic acid level or protein level, or may be subject to alternative splicing to result in a different polypeptide product. Such differences may, for example, be evidenced by a change in mRNA levels, surface expression, or secretion or other partitioning of a polypeptide.
  • Differential gene expression may include a comparison of expression between two or more genes or their gene products, or a comparison of the ratios of the expression between two or more genes or their gene products, or a comparison of two differently processed products of the same gene.
  • microarray refers to an ordered arrangement of hybridizable array elements on a substrate.
  • the term specifically includes polynucleotide microarrays, such as cDNA and oligonucleotide microarrays, and protein arrays.
  • a microarray is an array of thousands of individual gene (DNA) sequences immobilized in a known order on a solid support.
  • RNAs from different tissues are hybridized to the DNA on the chips.
  • An RNA molecule will only bind to the DNA from which it was expressed.
  • the relative expression of thousands of genes in biological samples e.g. normal and diseased tissue, tissue treated or untreated with a certain drug, etc.
  • protein sequences can be displayed on a microarray chip and used to study protein-protein interactions, or differences in protein levels in different biological samples, e.g. tissues.
  • polynucleotide generally refers to any polyribonucleotide or polydeoxribonucleotide, which may be unmodified RNA or DNA or modified RNA or DNA.
  • polynucleotides as defined herein include, without limitation, single- and double-stranded DNA, DNA including single- and double-stranded regions, single- and double- stranded RNA, and RNA including single- and double-stranded regions, hybrid molecules comprising DNA and RNA that may be single-stranded or, more typically, double-stranded or include single- and double-stranded regions.
  • polynucleotide as used herein includes triple-stranded regions comprising RNA or DNA or both RNA and DNA. The strands in such regions may be from the same molecule or from different molecules.
  • the term includes DNAs (including cDNAs) and RNAs that contain one or more modified bases.
  • DNAs or RNAs with backbones modified for stability or for other reasons are “polynucleotides” as that term is intended herein.
  • DNAs or RNAs comprising unusual bases, such as inosine, or modified bases, such as tritiated bases are included within the term “polynucleotides” as defined herein.
  • polynucleotide embraces all chemically, enzymatically and/or metabolically modified forms of unmodified polynucleotides, as well as the chemical forms of DNA and RNA characteristic of viruses and cells, including simple and complex cells.
  • oligonucleotide refers to a relatively short polynucleotide, including, without limitation, single-stranded deoxyribonucleotides, single- or double-stranded ribonucleotides, RNA:DNA hybrids and double-stranded DNAs.
  • transgenic animal and “transgenic mouse” as well we their grammatical equivalents, are used to refer to animals/mice deliberately produced to carry a gene from another animal. Transgenic animals specifically include transgenic rodents, such as, for example, mice, rats, guinea pigs, and the like.
  • xenotransplantation is used in the broadest sense and refers to the transfer of living cells, tissues or organs from one animal species into another, including humans.
  • B. Detailed Description The practice of the present invention will employ, unless otherwise indicated, conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, and biochemistry, which are within the skill of the art. Such techniques are explained fully in the literature, such as, "Molecular Cloning: A Laboratory Manual", 2 nd edition (Sambrook et al., 1989); “Oligonucleotide Synthesis” (M.J. Gait, ed., 1984); “Animal Cell Culture” (R.I.
  • the present invention provides a sensitive and reliable transgenic animal model for the study of tumor metastasis.
  • the present invention provides a reproducible mouse model of hepatic metastasis, which involves the introduction of mammalian (e.g. human) cancer cells into NOG mice.
  • NOG mice were developed at the Central Institute for Experimental Animals (CIEA, Kawasaki, Japan), and are also described in co-pending U.S. application Serial No. 10/221,549 filed on October 25, 2001, the entire disclosure of which is hereby expressly incorporated by reference.
  • NOD/SCID/ ⁇ c nu11 mice double homozygous for the severe combined immunodeficiency (SCID) mutation and interleukin-2R ⁇ (IL-2R ⁇ ) allelic mutation ( ⁇ c nu ") were generated by 8 backcross matings of C57BL/6J- ⁇ c nu " mice and NOD/Shi-scid mice.
  • SCID severe combined immunodeficiency
  • IL-2R ⁇ interleukin-2R ⁇ allelic mutation
  • NOD/SCID/ ⁇ c nu11 mice were described to be superior animal recipients for xenotransplantation, especially for human stem cell assays. For further details see, e.g. Hiramatsu et al, Blood 100:3175-82 (2002). It has now been found that the NOG mice are a superior mouse model for the study of human cancer metastasis.
  • this model can be used, for example, to screen and evaluate anti-cancer drugs and anti-metastasis drug candidates, and for the detection/screening of genes related to cancer metastasis, which, in turn, find utility in the diagnosis and/or treatment of metastatic cancer, and related conditions, including gene therapy treatment of metastatic cancer.
  • the mouse model of the present invention is suitable for modeling and studying any kind of metastasis, including hepatic, bone, brain, and lung metastasis.
  • Metastasis occurs in all types of cancers, including, without limitation, pancreatic cancer, prostate cancer, breast cancer, colorectal cancer, gastrointestinal cancer, colon cancer, lung cancer, hepatocellular cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, cancer of the urinary tract, thyroid cancer, renal cancer, carcinoma, melanoma, and brain cancer.
  • pancreatic cancer prostate cancer, breast cancer, colorectal cancer, gastrointestinal cancer, colon cancer, lung cancer, hepatocellular cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, cancer of the urinary tract, thyroid cancer, renal cancer, carcinoma, melanoma, and brain cancer.
  • cancer cells are transplanted into mice via tail vein injection, with or without prior immune-suppression, such as a sublethal dose of whole body irradiation and/or the administration of an immunosuppressant.
  • the cancer cells may be introduced into the animals by intrasplenic (portal vein) injection using an appropriate indwelling catheter.
  • Pulmonary metastasis can be established, for example, by intravenous injection of tumor cells into the recipient animals, for example as described in Worth and Kleinerman; Clin Exp. Metastasis 17:501-6 (1999).
  • the tumor cells may originate from tumor (cancer) cell lines, and from primary tumors (e.g. cancer) obtained from human or non-human subjects.
  • tumor metastasis macroscopic fragments of human fetal bone or mouse bone, may be implanted into NOG mice.
  • human tumor (cancer) cell lines or cells of primary tumors (cancer) can be injected either intravenously (colonization assay), or directly into the implanted tissue fragments.
  • Tumor metastasis can be monitored by methods known in the art, including various imaging techniques and histologic examination.
  • the NOG mice that have developed metastatic cancer can be treated with the test compound(s), and any change in the number, size or other properties of the metastatic nodules as a result of drug treatment, and the viability of the test animals are monitored relative to untreated and/or positive control, where the positive control typically is an animal treated with a know anti-metastatic compound.
  • the administration of the test compounds can be performed by any suitable route, including, for example, oral, transdermal, intravenous, infusion, intramuscular, etc. administration.
  • results obtained in this model can then be validated by follow-up pharmacokinetic, toxicologic, biochemical and immunologic studies, and ultimately human clinical studies.
  • the NOG mouse model can also be used to study targeted gene delivery to metastatic nodules in vivo, for example by portal vein infusion of a retro viral vector.
  • this NOG model can be used to study the feasibility of gene transfer to target tumor metastasis, to monitor the duration and level of gene expression and the degree of therapeutic effect, to optimize the dosing regimen and/or mode of administration, to study the dissemination of the gene transfer vector to non-targeted tissues (which provides information about potential toxicity), and the like.
  • Gene delivery most commonly is performed using retroviral vectors by techniques well known in the art.
  • Retroviruses are enveloped viruses containing a single stranded RNA molecule as their genome. Following infection, the viral genome is reverse transcribed into double stranded DNA, which integrates into the host genome where it is expressed.
  • the viral genome contains at least three genes: gag (coding for core proteins), pol (coding for reverse transcriptase) and env (coding for the viral envelope protein).
  • LTRs long terminal repeats
  • Retroviral vectors used in mouse models are most frequently based upon the Moloney murine leukemia virus (Mo-MLV).
  • lentiviruses can, for example, be used for gene transfer into experimental animals, such as NOG mice.
  • Gene delivery can also be performed by adenoviral vectors.
  • Adenoviroses are non- enveloped, icosahedral viruses with linear double-stranded DNA genomes. Adenoviruses infect non-dividing cells by interacting with cell surface receptors, and enter cells by endocytosis. Since the genome of adenoviruses cannot integrate with the host cell genome, the expression from adenoviral vectors is transient. Further details of the invention are illustrated by the following non-limiting examples.
  • Example 1 Study of hepatic metastasis of human pancreatic cancer Materials and Methods Male NOG mice and NOD/shiJic-sczd mice of 7-9 weeks, which had been obtained from the Central Institute for Experimental Animals (CIEA, Kawasaki, Japan), were used in this study. The animals were kept under specific pathogen-free conditions according to the Guideline for the Regulation of Animal Experimentation of CIEA. All human pancreatic cancer cell lines used in this study were obtained from the American Type Culture Collection (Rockville, MD,
  • DMEM fetal bovine serum
  • FBS Hyclone
  • BxPC-3, Capan-2 and PL45 were maintained a culture of RPMI1640 (SIGMA, Cat.No.D6046 or
  • the well- organized and reproducible hepatic metastases seen in NOG mice are useful in the study of hepatic metastasis of human pancreatic cancer and are expected to become the preferred model for screening and developing new anti-metastasis drugs. It was reported that the murine NK activity were compensatory very high in immunodeficient animals such as nude, SCID and NOD/SCID mice, and contributed to the low rate of tumor growth and cancer metastasis (Shpitz et al, Anticancer Res. 14(5A):1927-34 (1994)). In contrast, Ito et al.
  • Example 2 Detection of cancer metastasis related genes in cDNA microarray Materials and Methods Human pancreatic tumor cell lines, MIAPaCa-2, Panel, Capan2 and PL45 (available from ATCC) were cultured according to the method described in Example 1. Total RNA was extracted from confluent culture of those cells using TRIZOL reagent (GIBCO BRL). Cy-3 labeled cDNA probes were synthesized from 20 ⁇ G of total RNA using Atlas human IK specific primer set (BD), PowerScript labeling kit (BD), and Cy-3 fluorochrome (Amersham). Then, the probe was hybridized to the Atlas Glass Human 1.0 Microarray (BD) according to manufacturer's instructions.
  • the differentially expressed genes among the pancreatic tumor cell lines were globally searched using the Atlas Glass Human 1.0 Microarray (BD).
  • the Cy-3 labeled signals were detected and obtained and analyzed the corresponding images by aGM418 array scanner (Takara).
  • the data processing was carried out using Imagene Version 5.5 software.
  • MIAPaCa-2 and Panel cell lines were classified into a highly metastatic group, while the other cell lines, Capan2 and PL45, were classified into a non-metastatic group.
  • the average of the signal values from the "highly metastatic group” array was divided by the average of the signal values from the "non-metastatic group” array.
  • the resulting values are referred to as "gene expression levels", where a 10-fold difference and higher values were considered significant.
  • Results Gene expression profiles of each cell line were recorded in an EXCEL file
  • BRF1 butyrate response factor 1 gene
  • TIS1 IB protein prostate differentiation factor
  • PDF glycoproteins hormone ⁇ -subunit
  • thrombopoietin THPO
  • MFNG manic fringe homology
  • C5 complement component 5
  • JAG1 interleukin enhancer- binding factor
  • IGF- ⁇ PCAF-associated factor 65 alpha
  • NRF1 nuclear respiratory factor 1
  • SCF stem cell factor
  • PRDI-BF1 transcription factor repressor protein
  • SCYAl small inducible cytokine subfamily A member 1
  • transducin ⁇ 2 subunit X-ray repair complementing defective repair in Chinese hamster cells 1; putative renal organic anion transporter 1; Gl/S-specific cyclin E (CCNE); retinoic acid receptor- ⁇ (RARG); S-100 calcium- binding protein Al; neutral amino acid transporter A (SATT); dopachrome tautomerase; ets transcription factor (NERF2); calcium-activated potassium channel ⁇ -subunit; CD27BP; keratin 10; 6-O-methylguanine-DNA-methyltransferase (MGMT); xeroderma pigmentosum group A complementing protein (XPA); CDC6-related protein; cell division protein kinase 4; nociceptin receptor; cytochrome P450 XXVIIBl; N-myc proto-oncogene; solute carrier family member 1 (SLC2A1); membrane-associated kinase
  • the differential expression of the listed and other genes can be used, for example, in drug screening, to test anti-cancer and/or anti-metastatic drug candidates, and for diagnostic and therapeutic purposes, e.g. using gene transfer approaches.
  • All references cited herein are hereby expressly incorporated by reference in their entirety. While the present invention is illustrated by way of certain embodiments, it is not so limited. One skilled in the art will understand that various modifications are possible without substantially changing the operation of the invention. Thus, for example, the mouse model described herein can be replaced by other, equivalent animals models, in particular rodent, e.g. rat, models. All such modifications are intended to be within the scope of the invention.
  • mice Cell dose Autopsy No. of mice with metastasis Incidence (cells/head) (week) /total no. of mice (h) (%)
  • Ductal adenocarcinoma 1 ⁇ 10 4 6 0/10 0.0 pancreas NOD/SCID 1 ⁇ 10 5 6 0/ 8 0.0

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Abstract

La présente invention concerne un nouveau modèle de souris transgénique reproductible utile pour l'étude des métastases tumorales. Cette invention concerne plus particulièrement l'étude des métastases tumorales dans un modèle de souris transgénique NOD/SCID/ycnull .
PCT/US2004/019697 2003-07-10 2004-06-18 Modele animal utile pour l'analyse des metastases tumorales Ceased WO2005013682A2 (fr)

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AT04776817T ATE458997T1 (de) 2003-07-10 2004-06-18 Tiermodell zur analyse von tumormetastasierung
AU2004263079A AU2004263079A1 (en) 2003-07-10 2004-06-18 Animal model for the analysis of tumor metastasis
CA002531916A CA2531916A1 (fr) 2003-07-10 2004-06-18 Modele animal utile pour l'analyse des metastases tumorales
JP2006518659A JP4663634B2 (ja) 2003-07-10 2004-06-18 腫瘍転移の分析のための動物モデル

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006039678A3 (fr) * 2004-09-29 2006-08-24 Central Institue For Ex Animal CREATION DE LIGNEES CELLULAIRES CANCEREUSES HUMAINES AVEC POTENTIEL METASTATIQUE AU MOYEN DE SOURIS NOD/SCID/Ϝcnull (NOG)
JP2010522875A (ja) * 2007-03-27 2010-07-08 イミュノヴィア・アーベー 腺癌の検出のための蛋白質シグネチャー／マーカー
CN1920564B (zh) * 2005-08-26 2011-08-24 中国科学院上海生命科学研究院 细胞转录因子ilf-1的应用
US10301684B2 (en) 2011-02-11 2019-05-28 The Rockefeller University Treatment of angiogenesis disorders
US11248236B2 (en) 2015-06-23 2022-02-15 The Jackson Laboratory Non-HLA matched humanized NSG mouse model with patient-derived xenograft
US11320436B2 (en) 2020-07-16 2022-05-03 Immunovia Ab Methods, arrays and uses thereof
US11785923B2 (en) 2015-06-16 2023-10-17 The Jackson Laboratory Genetically modified non-human animals and methods relating to complement dependent cytotoxicity

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007139656A (ja) * 2005-11-21 2007-06-07 Igaku Seibutsugaku Kenkyusho:Kk 食道癌診断キット
WO2007138098A2 (fr) * 2006-05-31 2007-12-06 Projech Science To Technology, S.L. Modèles animaliers de métastases tumorales et toxicité
WO2010118782A1 (fr) * 2009-04-17 2010-10-21 Universite Libre De Bruxelles Procédés et outils pour prédire l'efficacité d'anthracyclines dans le traitement du cancer
US20130309246A1 (en) * 2011-02-02 2013-11-21 The Trustees Of Princeton University Jagged1 as a marker and therapeutic target for breast cancer bone metastasis
WO2013035779A1 (fr) * 2011-09-06 2013-03-14 国立大学法人東京大学 Procédé d'analyse d'interactions intercellulaires
WO2017142292A1 (fr) * 2016-02-15 2017-08-24 고려대학교 산학협력단 Procédé de production de modèle animal présentant un cancer du poumon
KR101992817B1 (ko) * 2016-02-15 2019-09-30 고려대학교 산학협력단 폐암 동물모델의 제조방법
RU2725273C1 (ru) * 2019-11-05 2020-06-30 федеральное государственное бюджетное учреждение "Национальный медицинский исследовательский центр онкологии" Министерства здравоохранения Российской Федерации Способ трансплантации фрагмента нейроэндокринной опухоли поджелудочной железы человека в поджелудочную железу иммунодефицитных мышей
PT118269A (pt) 2022-10-20 2024-04-22 Univ Aveiro Pkmyt1 for use in regenerative medicine

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7145055B2 (en) * 2000-12-01 2006-12-05 Central Institute For Experimental Animals Method of producing a mouse suitable for the engraftment, differentiation and proliferation of heterologous cells, mouse produced by this method and use of the mouse
US7135609B2 (en) * 2001-05-10 2006-11-14 Chugai Seiyaku Kabushiki Kaisha Non-human animal exhibiting bone metastasis of tumor cells and method of screening for bone metastasis inhibitors

Non-Patent Citations (25)

* Cited by examiner, † Cited by third party
Title
"Animal Cell Culture", 1987
"Current Protocols in Molecular Biology", 1987
"Gene Transfer Vectors for Mammalian Cells", 1987
"Handbook of Experimental Immunology", 1987, BLACKWELL SCIENCE INC.
"Methods in Enzymology", ACADEMIC PRESS, INC.
"Methods in Molecular Biology", vol. 209, article "Transgenic Mouse: Methods and Protocols"
"Molecular Cloning: A Laboratory Manual", 1989
"Oligonucleotide Synthesis", 1984
BRUNS ET AL., INT. J. CANCER, vol. 10:102, no. 2, 2002, pages 101 - 8
HIRAMATSU ET AL., BLOOD, vol. 100, 2002, pages 3175 - 82
HOTZ ET AL., PANCREAS, vol. 26, 2003, pages E89 - 98
IKEDA ET AL., JPN. J. CANCER RES., vol. 81, 1990, pages 987 - 93
ITO ET AL., BLOOD, vol. 100, 2001, pages 3221 - 8
ITO ET AL., BLOOD, vol. 100, 2002, pages 3175 - 82
JIMENEZ ET AL., ANN. SURG., vol. 231, 2000, pages 644 - 54
KHATIB, CANCER RES., vol. 62, 2002, pages 242 - 50
KUSAMA ET AL., GASTROENTEROLOGY, vol. 122, 2002, pages 308 - 17
NOMURA ET AL., CLIN. EXP. METASTASIS, vol. 19, 2002, pages 391 - 9
OHTA ET AL., JPN. 1. CANCER CHEMOTHER., vol. 23, 1996, pages 1669 - 72
SAITO ET AL., INT. IMMUNOL., vol. 14, 2002, pages 1113 - 24
SHISHIDO ET AL., SURG. TODAY, vol. 29, no. 6, 1999, pages 519 - 25
SHPITZ ET AL., ANTICANCER RES., vol. 14, no. 5A, 1994, pages 1927 - 34
TARBE ET AL., ANTICANCER RES., vol. 21, 2001, pages 3221 - 8
WORTH; KLCINCRMAN, CLIN EXP. METASTASIS, vol. 17, 1999, pages 501 - 6
YAHATA ET AL., 1. IMMUNOL., vol. 169, 2002, pages 204 - 9

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006039678A3 (fr) * 2004-09-29 2006-08-24 Central Institue For Ex Animal CREATION DE LIGNEES CELLULAIRES CANCEREUSES HUMAINES AVEC POTENTIEL METASTATIQUE AU MOYEN DE SOURIS NOD/SCID/Ϝcnull (NOG)
WO2006039671A3 (fr) * 2004-09-29 2006-10-12 Central Inst Exper Animals Marqueurs de genes de metastase tumorale
CN1920564B (zh) * 2005-08-26 2011-08-24 中国科学院上海生命科学研究院 细胞转录因子ilf-1的应用
JP2010522875A (ja) * 2007-03-27 2010-07-08 イミュノヴィア・アーベー 腺癌の検出のための蛋白質シグネチャー／マーカー
JP2017067792A (ja) * 2007-03-27 2017-04-06 イミュノヴィア・アーベー 腺癌の検出のための蛋白質シグネチャー／マーカー
US11525832B2 (en) 2007-03-27 2022-12-13 Immunovia Ab Protein signature/markers for the detection of adenocarcinoma
US10301684B2 (en) 2011-02-11 2019-05-28 The Rockefeller University Treatment of angiogenesis disorders
US12060619B2 (en) 2011-02-11 2024-08-13 The Rockefeller University Treatment of angiogenesis disorders
US11785923B2 (en) 2015-06-16 2023-10-17 The Jackson Laboratory Genetically modified non-human animals and methods relating to complement dependent cytotoxicity
US11248236B2 (en) 2015-06-23 2022-02-15 The Jackson Laboratory Non-HLA matched humanized NSG mouse model with patient-derived xenograft
US11320436B2 (en) 2020-07-16 2022-05-03 Immunovia Ab Methods, arrays and uses thereof

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